U.S. Pat. No. 3,681,354 discloses a class of dibenzo[b,f]oxepin-10-yl derivatives stated to have useful pharmacological properties including hypertensive, sedative, muscle relaxant, local anesthetic, analgesic, antipyretic and anti-inflammatory properties. The present invention is directed to certain coated pharmaceutical compositions containing the compound 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine described generically therein. This compound is a useful psychotropic agent and possesses particularly useful antipsychotic properties. The coated pharmaceutical compositions described herein are of particular value in providing therapeutically effective blood levels of this drug.
Prior to the present invention, the usefulness of this drug has been limited due to its degradation at low pH levels in the stomach, resulting in a poor and erratic absorption into the bloodstream. The compound 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine belongs to a class of enamines which is known to readily undergo hydrolytic cleavage in an aqueous acidic medium. Unfortunately, the compound 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine is no exception and possesses a high degree of acid lability under aqueous conditions resulting in the formation of the compound 2-chloro-dibenzo[b,f]oxepin-10-one as indicated below. ##STR1##
Under the normal conditions of gastric acidity, the pharmaceutically active compound undergoes hydrolytic cleavage with a concomitant loss of activity. It is well documented that the pH of the stomach contents can vary from 1.5 to 4 and that gastric residual time can range from less than 1 hour to 4 or more hours. Thus, the amount of undestroyed drug available at the site of absorption varies erratically from patient to patient depending upon such factors as amount and type of food intake, food composition and the rate of gastric emptying at the time of drug administration. Furthermore, the problem of absorbing the therapeutically active compound into the blood stream is compounded by the fact that this particular compound is soluble in aqueous solutions of low pH, precisely where the compound is most labile, whereas in aqueous solutions that have a pH greater than 7.5, the compound is insoluble.
The concept of using enteric coatings to protect drugs that are destroyed in gastric fluids is, of course, well known. Shellac and cellulose acetate phthalate meet most of the criteria of a good enteric coating and they are among the most widely used coating materials for this purpose. These coatings are generally designed to pass the drug intact or in concentrated form through the stomach, and to deliver the drug to the more alkaline sites of absorption in the small and lower intestine. Unfortunately, such enteric coatings are unsuitable for use with the compound 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine, inasmuch as they deliver the therapeutic agent to alkaline absorption sites where the compound is insoluble and poorly absorbed.
U.S. Pat. No. 4,001,390 discloses the use of hydroxypropyl methylcellulose phthalate coatings on solid dosage forms in combination with dyes and/or pigments so as to provide thin coating layers having a sufficient hiding power and providing a glossy and elegant finish. Such results are achieved by means of three successive coating layers, an undercoat containing the polymeric coating material, a secondary coat composed of the polymeric coating substance and a pigment, and a finish coat composed of the polymeric coating material. In contrast thereto the instant invention utilizes a single coating having a critical thickness of certain hydroxypropyl methylcellulose phthalate polymers to prepare duodenal soluble pharmaceutical compositions containing 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine suitable for oral administration. The coatings described herein are of such a nature as to protect the compound 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine from acid degradation in strongly acidic gastric fluids, but are designed to dissolve at the weakly acidic pH of 5.0 to 5.5 in order to permit dissolution and absorption of the drug substance.
U.S. Pat. No. 4,017,647 relates to the preparation of enteric coated dosage forms using an aqueous alkaline solution of certain polymeric substances including hydroxypropyl methylcellulose phthalate. Subsequent treatment of these coated dosage forms converts these polymeric coatings to a water-insoluble form stated to be suitable as enteric coatings. Such coatings, however, are ineffective for use with the particular therapeutic agent to which the invention relates due to the acid instability and the insolubility in neutral or alkaline aqueous solutions of the active ingredient.
I have discovered that the controlled use of a particular enteric coating material, viz, hydroxypropyl methylcellulose phthalate, results in the preparation of a duodenal-soluble coating which will sufficiently protect the compound 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine from acid degradation in gastric fluids, and yet will permit sufficient absorption of the compound to take place in the duodenum so as to be therapeutically useful. More particularly, I have discovered that these hydroxypropyl methylcellulose phthalate coatings dissolve at a pH of about 5.0 to 5.5, and when present at a coating thickness of about 0.1 mm to 0.2 mm, release the compound under the slightly acidic conditions of the duodenum, where the compound is sufficiently stable and yet sufficiently soluble so as to be available for absorption into the bloodstream of the treated patient.